For years, human papillomavirus (HPV) has been linked to numerous malignancies, among them cervical, anal, vaginal, vulvar, and penile cancer. More recently, a growing number of head-and-neck cancers have also been attributed to HPV. Traditionally, head-and-neck cancer—the sixth most common cancer worldwide—has been associated with tobacco and alcohol exposure. However, HPV-positive tumors now account for up to 65% of all head-and-neck cancers and up to 80% of oropharyngeal cancers, specifically.

The rapid increase in HPV-associated head-and-neck cancers may reflect increased awareness, improved techniques for identifying the virus in tumor tissue, or a true increase in prevalence, which in turn may reflect changes in patterns of sexual activity. Compared with HPV-negative cases, these tumors often present at a younger age and with more advanced disease due to involvement of regional lymph nodes. Nevertheless, numerous studies have suggested that HPV-positive head-and-neck cancers have better clinical outcomes. Superior progression-free survival and locoregional control rates have been attributed to the heightened antigenicity of these tumors, resulting in improved immune clearance. In addition, defects in DNA damage repair capacity and decreased hypoxia in the HPV-positive tumors increase their sensitivity to ionizing radiation.

Despite these observations, HPV status is not currently integrated into routine management decisions for this challenging disease. A number of clinical trials are examining the role of deintensified therapy for HPV-associated head-and-neck cancer, but even incremental modifications in treatment are not yet recommended outside the context of a clinical study.

Recent work by Seiwert et al. may considerably improve the understanding and treatment of HPV-associated head-and-neck cancer. To identify biological differences and new therapeutic targets, the authors performed massively parallel sequencing of more than 600 cancer-associated genes in 120 matched head-and-neck tumors and normal samples, in which almost 45% of the tumors were HPV-positive. HPV-negative cases had a mutational spectrum resembling that of lung squamous cell carcinoma, featuring mutations in TP53, CDKN2A, MLL2, CUL3, NSD1, PIK3CA, and NOTCH genes, as well as FGFR and EGFR amplifications. In contrast, HPV-positive cases harbored FGFR2/3 mutations (18%), KRAS mutations (6%), and DNA repair gene aberrations, including BRCA1/2 mutations (8%).

Moving forward, these findings may advance the care of both HPV-positive and -negative head-and-neck cancers. Several of the molecular alterations identified are targetable with monoclonal antibodies or small molecules currently in clinical use or development. The incorporation of such agents into therapeutic regimens will greatly expand patients’ options and hopefully improve outcomes.